Development of (6R)-2-Nitro-644-(trifluoromethoxy)phenoxy]-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine (DNDI-8219): A New Lead for Visceral Leishmaniasis

Discovery of the potent antileishmanial effects of antitubercular 6-nitro-2,3-dihydroimidazo [2,1-1)] [1,3]oxazoles and 7-substituted 2-nitro-5,6-dihydroimidazo[2,1-b][1,3]oxazines stimulated the examination of further scaffolds (e.g., 2-nitro-5,6,7,8-tetrahydroimidazo[2,1-b][1,3]oxazepines), but th...

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Published inJournal of medicinal chemistry Vol. 61; no. 6; pp. 2329 - 2352
Main Authors Thompson, Andrew M., O'Connor, Patrick D., Marshall, Andrew J., Blaser, Adrian, Yardley, Vanessa, Maes, Louis, Gupta, Suman, Launay, Delphine, Braillard, Stephanie, Chatelain, Eric, Wan, Baojie, Franzblau, Scott G., Ma, Zhenkun, Cooper, Christopher B., Denny, William A.
Format Journal Article
LanguageEnglish
Published WASHINGTON Amer Chemical Soc 22.03.2018
Subjects
Chemistry, Medicinal
Life Sciences & Biomedicine
Pharmacology & Pharmacy
Science & Technology
MYCOBACTERIUM-TUBERCULOSIS
PA-824
POTENTIAL ORAL TREATMENT
TROPICAL DISEASES
ANALOGS
PRECLINICAL CANDIDATE
ANTITUBERCULAR DRUG
SLEEPING SICKNESS
AFRICAN TRYPANOSOMIASIS
IN-VIVO ACTIVITIES
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Summary:Discovery of the potent antileishmanial effects of antitubercular 6-nitro-2,3-dihydroimidazo [2,1-1)] [1,3]oxazoles and 7-substituted 2-nitro-5,6-dihydroimidazo[2,1-b][1,3]oxazines stimulated the examination of further scaffolds (e.g., 2-nitro-5,6,7,8-tetrahydroimidazo[2,1-b][1,3]oxazepines), but the results for these seemed less attractive. Following the screening of a 900-compound pretomanid analogue library, several hits with more suitable potency, solubility, and microsomal stability were identified, and the superior efficacy of newly synthesized 6R enantiomers with phenylpyridine-based side chains was established through head-to-head assessments in a Leishmania donovani mouse model. Two such leads (R-84 and R-89) displayed promising activity in the more stringent Leishmania infantum hamster model but were unexpectedly found to be potent inhibitors of hERG. An extensive structure-activity relationship investigation pinpointed two compounds (R-6 and pyridine R-136) with better solubility and pharmacokinetic properties that also provided excellent oral efficacy in the same hamster model (>97% parasite clearance at 25 mg/kg, twice daily) and exhibited minimal hERG inhibition. Additional profiling earmarked R-6 as the favored backup development candidate.
ISSN:0022-2623
1520-4804
DOI:10.1021/acs.jmedchem.7b01581